HIV-infected women have higher rates of morbidity and mortality compared to men in the United States (U.S.). An important driver of health disparities and worse outcomes among HIV-infected women is food insecurity, or the inability to access food of sufficient quality or quantity in socially acceptable ways. Food insecurity affects 18 million households in the U.S. (40% of low income households), is more prevalent among women, and affects about half of urban poor HIV-infected individuals. Food insecurity is associated with worse immunologic and virologic outcomes in cross-sectional studies, increased HIV-related morbidity and mortality in longitudinal studies, and increased cardiovascular risk factors (hypertension, diabetes, and hyperlipidemia) in cross-sectional studies in the general population. Due to these negative health impacts among HIV-infected individuals, governmental and non-governmental organizations have argued to integrate food security and HIV/AIDS programming activities. A rigorous longitudinal study is urgently needed to quantify the impacts and identify the dominant mechanisms by which food insecurity negatively impacts health in order to improve the effectiveness and reach of food assistance programs and guide their integration with HIV/AIDS programs. The proposed research assembles experts from medicine, infectious disease, immunology, biostatistics, and nutrition for a 4-year longitudinal study to quantify the impacts and identify the pathways linking food insecurity to HIV treatment and cardiovascular health in the Women's Interagency HIV Study (WIHS). WIHS is an ongoing, prospective study in the U.S. of 1500 HIV-infected women and 650 non-infected, but at-risk, women. We plan to leverage the detailed HIV treatment and cardiovascular risk measures collected in WIHS to accomplish 3 aims. In aims 1 and 2, we hypothesize that food insecurity will be associated with worse HIV treatment and cardiovascular risk outcomes and that these relationships will be partially mediated by nutritional (food quality/quantity, obesity), mental health (depression, stress), and behavioral (treatment non-adherence, missed appointments) pathways. To accomplish aims 1 and 2, we will add measures of food insecurity, dietary quality, socio-economic status, competing demands between food and medical care, and antiretroviral (ARV) hair levels (a technique we pioneered as an objective measure of ARV adherence) to WIHS. Our analytic approach will be guided by a novel conceptual model that we recently published in the American Journal of Clinical Nutrition. In aim 3, we hypothesize that food insecurity will be associated with markers of gut microbial translocation (MT), inflammation and immune activation among HIV-infected women, and that this association will be mediated by diet, obesity, and worse HIV control. To accomplish aim 3, we will add measures of gut MT and immune activation for a sub-sample of 250 women on ARV therapy. Our work will be critical to attract funding for this priority issue. The ultimate goal of this work is to develop sustainable solutions to tackle the intersecting challenges of food insecurity and HIV/AIDS morbidity and mortality among women in the U.S. PUBLIC HEALTH RELEVANCE: Food insecurity is common among poor women and HIV-infected persons, and has been associated with more illness, higher risk of heart disease, and quicker decline to AIDS and death. The proposed study brings together a multidisciplinary team of experts for a 4-year study among over 2000 women to answer two key unresolved questions, namely What is the magnitude of the impact of food security on health? and Which mechanisms drive this impact? This research will be critical to a) help increase funding for the integration of HIV and nutrition programs in the U.S. and elsewhere; b) select among the various programmatic options for improving food insecurity among HIV-infected women; and c) improve the reach and effectiveness of existing supplemental nutritional assistance programs.